The invention concerns a device to stimulate living tissue with an array of microelectrodes.
Arrays of microelectrodes are used in neurophysiological or pharmacological applications for example. These arrays are used to record the electrical activity of a living tissue (cell or multicell activities). They are also used to stimulate a tissue electrically. This applies to any type of excitable tissue, notably nerve tissue, muscle e.g. cardiac tissue, or stem cells.
It is notably sought to be able to achieve focal stimulation of a nerve tissue. One long term application concerns neuroprostheses and targets the development of microstimulators to be implanted in the body (notably the human body but also in animal), to generate electric stimulations and compensate for the ill-functioning of neuron networks in the event of disease or anomaly of a body organ. The stimulations may for example be deep stimulations of the brain for neurodegenerative diseases (e.g. Parkinson's, Alzheimer, dementia), of the spinal cord in the event of motor disorders, or for the treatment of pain e.g. muscle pain or of sensory structures such as the peripheral nerves, retina, cochlea (inner ear) or other sensory relays.
To be able to stimulate living neurons, the array of microelectrodes must therefore be sized to the scale of the living tissue to be stimulated. Stimulation microelectrodes usually have a diameter in the order of a few tens of micrometres or less, and are spaced by a few hundred micrometres or less. However, for more macroscopic stimulation of the central or peripheral nervous system, larger electrodes (of mm or cm order) are used.
Documents [1] to [6] cited below, describe arrays of stimulation electrodes and methods for their use. The array may comprise several tens or even several hundred stimulation microelectrodes. Document [1) for example provides for an array with 36 stimulation microelectrodes and 4 reference electrodes. Document [5] makes provision for dividing the microelectrodes into two groups, one used for stimulation, the other used for recording, thereby doubling the number of microelectrodes.
One of the problems encountered with microelectrodes is to obtain focal stimulation of the living tissue. In an array of stimulation microelectrodes, if a stimulation signal is sent to one of the microelectrodes, it is to stimulate the region of the nerve tissue located facing this microelectrode.
Monopolar stimulations are known in which the stimulation of a living cell VIV is made between a stimulation microelectrode 11 from among the stimulation microelectrodes 10 of the array 1 and a remote ground RG of the array 1 of stimulation microelectrodes, as is illustrated in FIG. 1. With bipolar stimulation, as illustrated in FIG. 2, stimulation is made between two stimulation microelectrodes 11 and 12 of the array 1. These two types of stimulation are not fully satisfactory however, insofar as with monopolar stimulation, an electrode distant from a neuron can nevertheless activate this neuron with the same current as an electrode close to this neuron, and with bipolar stimulation, there is a blind spot where neurons close to the stimulating electrodes are not excited.
Document [8] WO 2005/087309 describes an arrangement of electrodes for the excitation of nerves or muscles, which consists of replacing large-size electrodes by a group of electrodes of smaller size occupying an overall space that is comparable to the space occupied by the large electrode. These groups form a single stimulation site. Each stimulation site comprises three or five groups each consisting of electrically conductive surface elements which are connected together via conductor lines. An array of electrodes comprises seven stimulation sites each having five groups each consisting of electrically conductive surface elements connected together via conductor lines. The use of groups of electrodes for each stimulation site allows more homogeneous potential distribution in the stimulated region opposite the stimulation site than obtained with a single, large-size electrode. This leads to homogenization of stimulations which is detrimental to their focusing.
Document [7] provides a method for preferential stimulation of neural somas, whereby a stimulation electrode is positioned in the vicinity of the region of neural tissue, the electrode comprising a first inner conductive region that is disk-shaped surrounded by a second conductive region that is ring-shaped, the first and second conductive regions being separated by an insulating region. The stimulation current is delivered between the central circular conductor and the ring conductor, this ring conductor providing a current return loop. The lateral dispersion of current in the neural tissue is contained within a more local region than with monopolar stimulation, which means that the number of somas activated by the electrode is limited, solely including those close to the central electrode. This device has the twofold disadvantage that the connections of the stimulation electrode need to be doubled, and higher currents need to be delivered in order to stimulate the local cells.
The invention sets out to overcome these disadvantages with an array of stimulation microelectrodes arranged in a determined side-by-side configuration and able to be selected for application of an electric stimulation signal by one of the microelectrodes. In particular, it must be possible for the stimulation device to be generalized to a large number of stimulation microelectrodes in the array, whilst being easy to implement.
For this purpose, the subject of the invention is a device to stimulate living tissue, comprising an array of microelectrodes arranged in a determined side-by-side configuration and selectable for application of an electric stimulation signal by one of the microelectrodes, the microelectrodes being insulated from each other and each comprising a conductor to send a stimulation signal, having a section for local application to the living tissue,
characterized in that, in addition to the microelectrode conductors, it comprises at least one supplemental conductive surface for application in whole or in part against the living tissue, this surface being insulated from the microelectrode conductors and comprising a plurality of conductive zones respectively located in the vicinity of a determined plurality of sections for local application of microelectrodes of the array,
connection means being provided to ensure electric connection between the conductive zones of the supplemental surface,
the supplemental conductive surface also being connected to at least one port intended to be connected to an external conductor returning at least part of the stimulation signal and being formed to ensure focal stimulation from at least one of the determined plurality of microelectrodes.
According to embodiments of the invention:                The supplemental conductive surface is integrated in the same support as that of the microelectrodes,        Or the supplemental conductive surface is integrated on a different support to that of the microelectrodes.        The supplemental conductive surface is in the form of a grid whose conductive zones are formed by meshes passing around microelectrodes, the connection means being formed on the supplemental surface by the intersections between meshes.        Said meshes passing around microelectrodes each surround a single microelectrode.        The grid is formed by rectilinear secant lines.        Each of the meshes of the grid surrounding a microelectrode forms a stimulation pixel restricted to the space delimited by this mesh.        The supplemental conductive surface passes between microelectrodes.        The supplemental conductive surface surrounds microelectrodes.        The supplemental conductive surface is continuous with openings for passage of the local application sections of microelectrodes.        The supplemental conductive surface comprises electrically parallel branches between microelectrodes and each passing in the vicinity of several microelectrodes.        The electric connection means between the different conductive zones are located at least in part in the supplemental conductive surface.        The electric connection means are located at least in part outside the supplemental conductive surface, inside or outside a support of the supplemental conductive surface or in a supplemental external electric circuit.        The supplemental conductive surface has interface surface electric conductivity (interface conductivity between the electrode and the tissue) of 100 S/m2 or higher at a frequency of 100 Hz to 1,000 Hz.        The supplemental conductive surface has interface surface electric conductivity (interface conductivity between the electrode and the tissue) of 1,000 S/m2 or higher at a frequency of 100 Hz to 1,000 Hz, and preferably 40,000 S/m2 or higher at a frequency of 100 Hz to 1,000 Hz.        The array of microelectrodes has a spacing pitch between microelectrodes, and said conductive zones of the supplemental surface pass at a distance from the plurality of microelectrodes that is equal to or less than five times the maximum spacing pitch between micro electrodes, and preferably at a distance equal to or less than the minimum spacing pitch between microelectrodes.        Said conductive zones of the supplemental surface pass at a distance from the plurality of microelectrodes that is equal to or less than 500 μm.        The device comprises a multiplicity of electric ports for access to the microelectrodes, which are respectively associated with the multiplicity of microelectrodes of the array, the port of the supplemental conductive surface 3 being single and separate from the electric ports of the microelectrodes.        The device comprises a multiplicity of electric ports for access to the microelectrodes, which are respectively associated with the multiplicity of microelectrodes of the array, the port of the supplemental conductive surface being multiple and separate from the electric ports of the microelectrodes.        The device comprises a multiplicity of electric ports for access to the microelectrodes, which are respectively associated with the multiplicity of microelectrodes of the array, the port of the supplemental conductive surface being single and separate from the electric ports of the microelectrodes, for each supplemental conductive surface if there is a plurality thereof.        The microelectrodes located on the edge of the array delimit a region for application against the living tissue, and the edge or port of the supplemental conductive surface is located outside the application region of the microelectrodes.        The device further comprises a first system to generate electric stimuli or stimulation currents and to deliver these to the tissue via the microelectrodes, and also to amplify and multiplex the signals recorded with the microelectrodes. This system is connected to the microelectrodes and to the surface port. The device also comprises a second system for acquisition and control provided with a man-machine interface to control the first system for the purposes of sending to at least one preselected microelectrode a predetermined stimulation signal on the man-machine interface, and to collect the activity of the living tissue responding or not responding to the stimulation signal for its reproduction on the man-machine interface.        The microelectrodes located on the edge of the array delimit a region for application against the living tissue, and the surface port is located inside the application region of the microelectrodes.        The device is implemented in contact with a living tissue, or part of a living organ, in vivo or in vitro, a cell preparation, an explant, a living organism, a laboratory system, an isolated living organ, part of an isolated living organ, or an implant for a living being.        
A second subject of the invention is a removable assembly intended to be mounted in the device such as described above characterized in that, on one same removable module or distributed over several separate removable modules, it comprises the array of microelectrodes, said supplemental surface, an input-output electric interface circuit for electric connection of the microelectrodes and of the supplemental surface with the outside, comprising a multiplicity of electric terminals for access respectively to the multiplicity of microelectrodes of the array and a terminal for access to the supplemental surface separate from the electric terminals of the microelectrodes. A third subject of the invention is use of the device such as described above for the recording of signals emitted by a living tissue.